Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
  • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

• This invention relates to a pharmaceutical formulation, more particularly to a tablet containing a novel polymorph of a macrolide antibiotic.
• Dirithromycin is a macrolide antibiotic derived from erythromycin.
• the antibiotic is described in U.S. Patent No. 4,048,306 and has the chemical name, Erythromycin, 9-deoxo-11-deoxy-9,11-[imino[2-(2-methoxyethoxy)ethylidene]oxy]-, [9S,16R].
• Dirithromycin prepared by the method described in U.S. Patent No. 4,048,306 is produced in the form of a polymorph which is hereinafter referred to as "Form I".
• D represents the interplanar spacing and I/I o the relative intensity: D( ⁇ ) I/I o 11.28 1.00 9.81 0.35 8.53 0.76 7.67 0.23 7.12 0.02 6.94 0.02 6.66 0.10 6.39 0.09 5.97 0.21 5.65 0.69 5.42 0.67 5.18 0.23 4.98 0.08 4.83 0.31 4.64 0.07 4.43 0.40 4.26 0.17 4.14 0.05 4.06 0.15 3.86 0.15 3.76 0.17 3.62 0.10 3.50 0.08 3.43 0.03 3.35 0.07 3.04 0.07 2.95 0.02 2.88 0.02 2.84 0.02 2.71 0.03 2.66 0.02 2.58 0.03
• Form I is metastable and is therefore not well suited for use in pharmaceutical formulations such as tablets.
• a tablet containing dirithromycin Form II as an active ingredient containing dirithromycin Form II as an active ingredient.
• the tablet will also, of course, contain one or more pharmaceutically-acceptable excipients, such as binders, lubricants, disintegrants, fillers, etc.
• This new polymorph has essentially the following x-ray powder diffraction pattern, wherein D represents the interplanar spacing and I/I o the relative intensity: D( ⁇ ) I/I o 14.17 0.02 11.96 0.27 10.43 0.11 9.65 1.00 8.86 0.84 8.18 0.54 7.07 0.33 6.99 0.10 6.84 0.21 6.59 0.03 6.24 0.05 6.07 0.29 5.97 0.19 5.77 0.06 5.54 0.36 5.50 0.47 5.45 0.26 5.13 0.22 5.11 0.29 4.84 0.29 4.75 0.47 4.72 0.42 4.50 0.62 4.44 0.31 4.24 0.20 4.20 0.05 4.11 0.17 4.09 0.18 3.92 0.14 3.87 0.12 3.83 0.12 3.73 0.06 3.55 0.08 3.49 0.15 3.46 0.07 3.42 0.11 3.33 0.05 3.17 0.04 3.11 0.02 2.96 0.04 2.83 0.02 2.74 0.04 2.57 0.03
• Form II Since the active ingredient of the tablet (Form II) is to be used as a pharmaceutical it should be in a pharmaceutical state of purity. For stability purposes, Form II should not contain substantial amounts of Form I. Preferably, Form II should be associated with less than 10% of Form I, most preferably less than 5%.
• Dirithromycin is a very effective antibiotic and has considerable advantages over other macrolide antibiotics since it need only be administered once a day in a total dosage of up to 500 mg.
• some care is needed in the design of orally acceptable formulations since the compound is sensitive to acidic media such as present in the stomach.
• the tablet of the invention be coated by a layer resistant to gastric juices, i.e. an "enteric coating".
• enteric coating a layer resistant to gastric juices
• a lacquer is used to form the coating.
• a 20 g portion of non-solvated dirithromycin was added to a solvent mixture comprised of 81 ml acetone and 9 ml water.
• the solution was heated to about 60°C.
• the solution was maintained at 60°C until the reaction volume was 35 ml.
• An additional 100 ml portion of water was added slowly over 1 hour.
• the mixture was allowed to cool to room temperature.
• the cooled mixture was placed in an ice bath and stirred for 1 hour.
• the solid was isolated by filtration, and rinsed with 25 ml of chilled solvent comprised of 67% water and 33% acetone.
• the solid was rinsed with a 40 ml portion of water at ambient temperature.
• the wet cake of acetone solvate of dirithromycin was left at ambient conditions overnight.
• a 10.0 g sample of acetone solvate of dirithromycin was added with stirring to 100 ml of water with nitrogen purge. The temperature of the reaction mixture was increased to 74°C and stirred at about 72-75°C for 4 hours. The mixture was vacuum filtered and washed with about 35 ml of 60°C water. The solid was dried in vacuo at 50°C overnight. The solid was identified as Form II dirithromycin, by x-ray powder diffractometry. The total yield of the reaction was 8.74 g (87.4%).
• the following data relates to a tablet containing 250 mg of dirithromycin Form II as the active ingredient.
• Core Tablet MG/Tablet Dirithromycin Form II 250.0 mg Magnesium Carbonate 250.0 mg Microcrystalline Cellulose 199.6 mg Sodium Starch Glycolate 10.0 mg Hydroxypropyl Cellulose 15.0 mg Croscarmellose Sodium 10.0 mg Magnesium Stearate 12.0 mg Subcoating Hydroxypropyl Methylcellulose 2910 (E-5) 16.21 mg Polyethylene Glycol (3350) 4.63 mg Propylene Glycol 6.95 mg Benzyl Alcohol 2.31 mg Enteric Coating Methacrylic Acid Copolymer Aqueous Dispersion (L30D) (Solids) 48.65 mg Color Mixture White T3166-WE (Solids) 20.31 mg Triethyl Citrate 1.65 mg Talc Trace
• the lots may be prepared as a single entity or fraction thereof and all units blended as a dry mix before compression. All ingredients are security sieved. Dirithromycin (Form II), magnesium carbonate, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose, and magnesium stearate are thoroughly blended in a ribbon mixer or other type of suitable mixer such as a V-blender, conical mixer, etc. The resulting powder mixture is compacted using a roller compactor or equivalent dry granulating equipment. The granulation is sized if necessary using an oscillating granulator, fitz mill or other suitable milling equipment.
• the sized granulation is blended with additional microcrystalline cellulose, croscarmellose sodium, and magnesium stearate in a ribbon mixer or other type of suitable mixer such as a V-blender, conical mixer, etc. After blending, the weight is checked against theoretical. The granulation is compressed on a conventional type compression machine such as a Manesty Betapress, etc. weight checks of the core tablets are made routinely throughout the compression process and the samples are pooled for testing.
• the subcoating is prepared by dissolving hydroxypropyl methylcellulose 2910 (E-5), polyethylene glycol, propylene glycol and benzyl alcohol in purified water.
• This coating solution can be prepared using a Groen kettle, stockpot, or equivalent and a means to provide agitation such as a Lightening mixer or equivalent.
• This coating solution is applied to the core tablets from above in an Accela Cota coating pan or equivalent film coating equipment.
• Suitable spraying systems such as the Accela-Spray II, Nordson spray unit, Graco spray unit or equivalent spraying equipment are utilized. Alternate spraying and drying cycles are used if necessary until the desired amount of coating solution has been applied.
• the enteric coating suspension is prepared by mixing methacrylic acid copolymer aqueous dispersion (L30D), color mixture white T3166-WE, and triethyl citrate with purified water.
• This coating suspension can be prepared using a Groen kettle, stockpot, or equivalent and a means to provide agitation such as a Lightning mixer or equivalent.
• This coating suspension is applied to the subcoated tablets from above in an Accela Cota coating pan or equivalent film coating equipment. Suitable spraying systems such as the Accela-Spray II, Nordson spray unit, Graco spray unit or equivalent spraying equipment are utilized. Alternate spraying and drying cycles are used if necessary until the desired amount of coating suspension has been applied.
• the tablets may be finished by dusting lightly with talc (to increase the luster of the coated tablets). Only trace amounts of this polishing agent adheres to the finished tablets.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Organic Chemistry (AREA)
• Epidemiology (AREA)
• Molecular Biology (AREA)
• Engineering & Computer Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biochemistry (AREA)
• Biotechnology (AREA)
• Genetics & Genomics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Saccharide Compounds (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Steroid Compounds (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Formation And Processing Of Food Products (AREA)

Applications Claiming Priority (2)

Publications (2)

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Country Status (27)

Families Citing this family (8)

Family Cites Families (4)

• 1992
  • 1992-04-15 ZA ZA922777A patent/ZA922777B/xx unknown
  • 1992-04-15 ZA ZA922776A patent/ZA922776B/xx unknown
  • 1992-04-24 YU YU44392A patent/YU44392A/sh unknown
  • 1992-04-24 YU YU44492A patent/YU44492A/sh unknown
  • 1992-04-24 IL IL10170592A patent/IL101705A/en active IP Right Grant
  • 1992-04-27 KR KR1019920007117A patent/KR100193742B1/ko not_active IP Right Cessation
  • 1992-04-27 CA CA002067275A patent/CA2067275C/en not_active Expired - Fee Related
  • 1992-04-27 ES ES92303752T patent/ES2088098T3/es not_active Expired - Lifetime
  • 1992-04-27 IL IL101704A patent/IL101704A/en not_active IP Right Cessation
  • 1992-04-27 RU SU925011639A patent/RU2070203C1/ru not_active IP Right Cessation
  • 1992-04-27 NZ NZ242505A patent/NZ242505A/xx not_active IP Right Cessation
  • 1992-04-27 BR BR929201541A patent/BR9201541A/pt not_active Application Discontinuation
  • 1992-04-27 DK DK92303752.7T patent/DK0511799T3/da active
  • 1992-04-27 EP EP92303752A patent/EP0511799B1/en not_active Expired - Lifetime
  • 1992-04-27 CY CY194692A patent/CY1946A/xx unknown
  • 1992-04-27 DE DE69214710T patent/DE69214710T2/de not_active Expired - Fee Related
  • 1992-04-27 EP EP92303753A patent/EP0511800B1/en not_active Expired - Lifetime
  • 1992-04-27 ES ES92303753T patent/ES2093779T3/es not_active Expired - Lifetime
  • 1992-04-27 CN CN92103161A patent/CN1069197C/zh not_active Expired - Fee Related
  • 1992-04-27 NO NO921616A patent/NO180450C/no unknown
  • 1992-04-27 IE IE921345A patent/IE74885B1/en not_active IP Right Cessation
  • 1992-04-27 FI FI921876A patent/FI921876A/fi not_active Application Discontinuation
  • 1992-04-27 IE IE921346A patent/IE76296B1/en not_active IP Right Cessation
  • 1992-04-27 JP JP04107514A patent/JP3135672B2/ja not_active Expired - Fee Related
  • 1992-04-27 NZ NZ242506A patent/NZ242506A/xx not_active IP Right Cessation
  • 1992-04-27 CZ CS921277A patent/CZ282218B6/cs not_active IP Right Cessation
  • 1992-04-27 MY MYPI92000718A patent/MY114226A/en unknown
  • 1992-04-27 FI FI921877A patent/FI101795B/fi active
  • 1992-04-27 HU HU9201398A patent/HU213613B/hu not_active IP Right Cessation
  • 1992-04-27 DK DK92303753.5T patent/DK0511800T3/da active
  • 1992-04-27 JP JP10732592A patent/JP3333545B2/ja not_active Expired - Fee Related
  • 1992-04-27 MY MYPI92000719A patent/MY109498A/en unknown
  • 1992-04-27 CA CA002067274A patent/CA2067274C/en not_active Expired - Fee Related
  • 1992-04-27 MX MX9201946A patent/MX9201946A/es not_active IP Right Cessation
  • 1992-04-27 AT AT92303752T patent/ATE138924T1/de not_active IP Right Cessation
  • 1992-04-27 NO NO921617A patent/NO179504C/no unknown
  • 1992-04-27 KR KR1019920007116A patent/KR100194307B1/ko not_active IP Right Cessation
  • 1992-04-27 BR BR929201540A patent/BR9201540A/pt not_active Application Discontinuation
  • 1992-04-27 CN CN92103160A patent/CN1030611C/zh not_active Expired - Fee Related
  • 1992-04-27 HU HU9203168A patent/HU215917B/hu not_active IP Right Cessation
  • 1992-04-27 RU SU925011642A patent/RU2045953C1/ru not_active IP Right Cessation
  • 1992-04-27 CZ CS921276A patent/CZ282021B6/cs not_active IP Right Cessation
  • 1992-04-27 AT AT92303753T patent/ATE144425T1/de not_active IP Right Cessation
  • 1992-04-27 MX MX9201944A patent/MX9201944A/es unknown
  • 1992-04-27 DE DE69211220T patent/DE69211220T2/de not_active Expired - Fee Related
  • 1992-04-28 AU AU15257/92A patent/AU655978B2/en not_active Ceased
  • 1992-04-28 AU AU15255/92A patent/AU646734B2/en not_active Ceased
  • 1992-06-09 TW TW081103332A patent/TW216399B/zh active
  • 1992-06-09 TW TW081103328A patent/TW315371B/zh active
• 1996
  • 1996-07-02 GR GR960401812T patent/GR3020439T3/el unknown
  • 1996-08-08 HK HK153696A patent/HK153696A/xx not_active IP Right Cessation
  • 1996-11-20 GR GR960403099T patent/GR3021706T3/el unknown
  • 1996-12-12 HK HK215096A patent/HK215096A/xx not_active IP Right Cessation
• 1997
  • 1997-09-05 CY CY197597A patent/CY1975A/xx unknown

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